Method and apparatus for the transdermal administration of a substance

ABSTRACT

A transdermal delivery device includes a plurality of microneedles for injecting a substance such as a pharmaceutical agent into or below the stratum corneum of the skin. The device has housing formed from a top and bottom wall to define a chamber for containing a pharmaceutical agent. An inlet port is provided in the top wall of the housing for supplying the pharmaceutical agent to the chamber and directing the agent to the microneedles. The housing can have a Luer lock type fitting for coupling with a syringe having a Luer lock collar to inject the pharmaceutical agent into the housing. The housing can be divided into a plurality of chambers by an internal wall for supplying different agents simultaneously or sequentially to a patient. The microneedles have a length of about 5-250 microns and generally about 50-100 microns.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 10/441,035 filed on May 20, 2003 which is a continuation ofU.S. patent application Ser. No. 09/401,452 filed on Sep. 22, 1999, nowU.S. Pat. No. 6,623,457 issued on Sep. 23, 2003.

FIELD OF THE INVENTION

The present invention relates to a method and apparatus for delivering asubstance and particularly a pharmaceutical agent transdermally to apatient. More particularly, the invention is directed to a method andapparatus for delivering a pharmaceutical agent such as a vaccine to apatient through the stratum corneum.

BACKGROUND OF THE INVENTION

The skin is made up of several layers with the upper composite layerbeing the epithelial layer. The outermost layer of the skin is thestratum corneum which has well known barrier properties to preventmolecules and various substances from entering the body and analytesfrom exiting the body. The stratum corneum is a complex structure ofcompacted keratinized cell remnants having a thickness of about 10-30microns. The stratum corneum forms a waterproof membrane to protect thebody from invasion by various substances and the outward migration ofvarious compounds.

The natural impermeability of the stratum corneum prevents theadministration of most pharmaceutical agents and other substancesthrough the skin. Numerous methods and devices have been proposed toenhance the permeability of the skin and to increase the diffusion ofvarious drugs through the skin so that the drugs can be utilized by thebody. Typically, the delivery of drugs through the skin is enhanced byeither increasing the permeability of the skin or increasing the forceor energy used to direct the drug through the skin.

One example of a method for increasing the delivery of drugs through theskin include iontophoresis. Iontophoresis generally applies an externalelectrical field to ionize the drug, thereby increasing the diffusion ofthe drug through the skin. Iontophoresis can be difficult to control theamount and rate of drug delivery. Under some circumstances,iontophoresis can cause skin damage depending on the extent ofionization, the energy applied to ionize the drug and duration of thetreatment.

Sonic, and particularly ultrasonic energy, has also been used toincrease the diffusion of drugs through the skin. The sonic energy istypically generated by passing an electrical current through apiezoelectric crystal or other suitable electromechanical device.Although numerous efforts to enhance drug delivery using sonic energyhave been proposed, the results generally show a low rate of drugdelivery.

Another method of delivering drugs through the skin is by formingmicropores or cuts through the stratum corneum. By penetrating thestratum corneum and delivering the drug to the skin in or below thestratum corneum, many drugs can be effectively administered. The devicesfor penetrating the stratum corneum generally include a plurality ofmicron size needles or blades having a length to penetrate the stratumcorneum without passing completely through the epidermis. Examples ofthese devices are disclosed in U.S. Pat. No. 5,879,326 to Godshall etal.; U.S. Pat. No. 5,250,023 to Lee et al., and WO 97/48440.

Transdermal drug delivery is also known to use pulsed laser light toablate the stratum corneum without significant ablation or damage to theunderlying epidermis. A drug is then applied to the ablated area andallowed to diffuse through the epidermis.

The prior methods and apparatus for the transdermal administration ofdrugs has exhibited limited success. Accordingly, a continuing needexists in the industry for an improved device for the administration ofvarious drugs and other substances.

SUMMARY OF THE INVENTION

The present invention is directed to a method and apparatus for thetransdermal delivery of a substance, such as a drug, vaccine or otherpharmaceutical agent, to a patient. In particular, the invention isdirected to a method and apparatus for delivering a pharmaceutical agentto the stratum corneum of the skin to a sufficient depth where thepharmaceutical agent can be absorbed and utilized by the body. Inembodiments where the pharmaceutical agent is a vaccine, the vaccine isintroduced into the intradermal tissue below the stratum corneum wherethe vaccine can generate an immune response.

Accordingly, a primary object of the invention is to provide a methodand apparatus for efficiently administering a pharmaceutical agenttransdermally through the skin substantially without pain to thepatient.

Another object of the invention is to provide an apparatus having aplurality of microneedles or blades for penetrating the stratum corneumof the skin for delivering a pharmaceutical agent or other substance tothe skin.

A further object of the invention is to provide an apparatus fordelivering a plurality of drugs transdermally to an animal eithersimultaneously or sequentially.

Another object of the invention is to provide a method for transdermallydelivering one or more vaccines simultaneously or sequentially in smalldoses.

A further object of the invention is to provide a method and apparatusfor the transdermal delivery of multiple vaccines without the need forvaccine reformulation or combination.

A still further object of the invention is to provide an apparatus forthe transdermal delivery of a pharmaceutical agent having a plurality ofmicroneedles for penetrating the stratum corneum and a coupling memberfor coupling with a supply container for supplying a pharmaceuticalagent to the microneedles.

Another object of the invention is to provide an apparatus having aplurality of microneedles for penetrating the stratum corneum and anouter adhesive patch for adhesively attaching the apparatus to the skinof a patient.

Still another object of the invention is to provide a transdermalpharmaceutical delivery device having an array of microneedles forpenetrating the stratum corneum of the skin, where the device has achannel in a bottom surface for directing a fluid containing apharmaceutical agent from a source to the microneedles.

A further object of the invention is to provide a device for thetransdermal delivery of a substance to a patient where the device has anarray of microneedles and a dried substance, the dried substance beingreconstituted by introducing a solvent or carrier through the device andthen delivered to a patient.

These and other objects of the invention are substantially attained byproviding an intradermal delivery device for introducing a substanceinto the skin of a patient. The device comprises a top wall having a topsurface, a bottom surface, and at least one opening extending betweenthe top and bottom surfaces. A bottom wall is coupled to the top walland spaced therefrom to define a reservoir therebetween for containingthe substance. The bottom wall has an inner surface and an outer surfacewhich have a plurality of openings. A coupling member is attached to thetop surface of the top wall for supplying the substance through theopenings in the top wall and into the reservoir. A plurality ofmicroneedles are coupled to the outer surface of the bottom wall and arein communication with the openings in the bottom wall for directing thesubstance from the reservoir to the skin of a patient. The microneedleshave a length sufficient to penetrate the stratum corneum of the skinwithout piercing or passing completely through the epidermis. The actuallength of the microneedles can vary to optimize the delivery for theparticular substance being administered. For example, the microneedlesfor administering a vaccine can have a length to pass through thestratum corneum into the other skin layers where deposition of vaccineand/or adjuvant can generate a desired immune response. This wouldnormally follow interaction or uptake with various mechanisms thatproduce such responses, for example, uptake and antigen processing byLangerhans cells.

The objects and advantages of the invention are further attained byproviding an intradermal device for administering a pharmaceutical agentthrough the skin of a patient. The device comprises a substantiallyplanar base having a top surface, a bottom surface and an openingextending between the top and bottom surfaces. A coupling member isattached to the top surface of the base for directing a fluid containinga pharmaceutical agent through the opening in the base and for couplingto a fluid source. A plurality of microneedles are attached to andextend from the bottom surface of the base and have a length sufficientto penetrate the stratum corneum of the skin. A plurality of channelsare formed in the bottom surface of the base and extend from the openingoutwardly toward an outer edge of the base. The channels are positionedbetween the microneedles for directing a fluid from the opening to themicroneedles.

The objects of the invention are further attained by providing anintradermal delivery device for delivering a substance, such as apharmaceutical agent, to a patient. The device comprises a syringehaving a syringe barrel with an outlet tip and a plunger for dispensinga liquid in the syringe. A plurality of microneedles are coupled to thetip. The microneedles can have a length sufficient to penetrate thestratum corneum of the skin and have channels which extend through themicroneedles for delivering the pharmaceutical agent to a patient.

Another object of the invention is to provide a method of administeringa pharmaceutical agent through the skin of a patient which comprisesproviding an intradermal device having a body with a top surface, abottom surface, and at least one opening extending between the top andbottom surfaces. A plurality of microneedles are attached to and extendfrom the bottom surface of the body and can have a length sufficient topenetrate the stratum corneum of, the skin. The device contacts the skinof a patient and sufficient pressure is applied for the microneedles topenetrate the stratum corneum of the patient. A pharmaceutical agent orother substance is delivered to the microneedles so that the substanceis absorbed through the skin.

The objects, advantages and other salient features of the invention willbecome apparent from the following detailed description which, taken inconjunction with the annexed drawings, discloses preferred embodimentsof the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The following is a brief description of the drawings in which:

FIG. 1 is a side elevational view in cross-section of a transdermaldelivery device in accordance with a first embodiment of the invention;

FIG. 2 is a bottom view of the transdermal delivery device of FIG. 1with the cover removed;

FIG. 3 is a side view of the transdermal delivery device of FIG. 1showing a syringe for supplying the device with a pharmaceutical agent;

FIG. 3A is a partial side view in cross-section of the microneedles;

FIG. 4 is a partial side view of a transdermal delivery device accordingto a further embodiment of the invention, showing microneedles ofdifferent length;

FIG. 5 is top view of the transdermal delivery device of FIG. 4;

FIG. 6 is side elevational view in partial cross-section showing asupply container for supplying the device of FIG. 4 with apharmaceutical agent;

FIG. 7 is a bottom view of the transdermal delivery device of FIG. 4,showing the channels for directing the pharmaceutical agent from thesupply container to the microneedles;

FIG. 8 is a side view of a further embodiment of the invention, in whicha syringe barrel is provided with a microneedle tip; and

FIG. 9 is a partial cross-sectional side view of a further embodiment ofthe invention, in which a syringe with a Luer lock collar is coupled toa delivery device having a plurality of microneedles.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed to an intraepidermal delivery devicefor administering a substance to a patient. More particularly, theinvention is directed to a delivery device and to a method foradministering a substance into or below the stratum corneum of the skinof a patient. As used herein, the term penetrate refers to entering alayer of the skin without necessarily passing completely through.Piercing refers to passing completely through a layer of the skin. Asused herein, transdermal refers to the delivery of a substance, such asa pharmaceutical, biological agent or vaccine, through one or morelayers of skin. Intradermal refers to one or more layers within the skinand not limited to the dermis layer of the skin.

The device and method of the present invention are particularly suitablefor use in administering various substances, including pharmaceuticalagents, to a patient, and particularly to a human patient. As usedherein, a pharmaceutical agent includes a substance having biologicalactivity that can be delivered through the body membranes and surfaces,and particularly the skin. Examples include antibiotics, antiviralagents, analgesics, anesthetics, anorexics, antiarthritics,antidepressants, antihistamines, anti-inflammatory agents,antineoplastic agents, vaccines, including DNA vaccines, adjuvants,biologics, and the like. Other substances which can be deliveredintradermally to a patient include proteins, peptides and fragmentsthereof. The proteins and peptides can be naturally occurring,synthesized or recombinantly produced.

In some embodiments of the present invention, a vaccine is administeredusing the device and method of the invention. The multipuncture deviceof the invention is believed in addition to have a unique immunologicaladvantage in the delivery of vaccines with the potential of increasingthe vaccine's clinical value. The insertion of the multiple needlepoints into the tissue is suggested as having an adjuvant-likestimulatory effect. The needle stick response from multiple microneedlepoints is believed more than a simple acute inflammatory response.Needle sticks can cause damage to a variety of cells and cellulararchitecture, causing the appearance of polymorphonuclear neutrophil(PMN) and microphages as well as the release of cytokines, includingILI, tumor necrosis factor (TNF) and other agents, which can lead to anumber of other immunological responses. The soluble stimulatory factorsinfluence the proliferation of lymphocytes and are central to the immuneresponse to vaccines. The immune stimulation is proportional to thedirect needle-cell interaction.

The microneedle device of the present invention is valuable in promotingsignificant immune response to a vaccine by delivering a vaccine belowthe stratum corneum and into the cells of the tissue. The microneedlescan have a length to penetrate and pass through the stratum corneumwithout penetrating the dermis to minimize absorption of the vaccineinto the bloodstream. The small intracellular depots created by themicroneedle array are believed to increase the availability of thevaccine antigen for interaction with antigen presenting cells more thanwould a vaccine deposited by standard needles in a larger depotquantity. In further embodiments, the microneedles can have a length topenetrate, but not pierce, the stratum corneum.

The microneedle array of the invention is believed to magnifyseveral-fold the trivial or inconsequential immune stimulatory impact ofa single needlestick independent of the route of delivery and vaccine.The microneedle delivery device facilitates and enhances vaccineimmunogenicity by an adjuvant-like immune stimulation.

The primary barrier properties of the skin including the resistance todrug penetration reside in the outermost layer of the skin, referred toas the stratum corneum. The inner layers of the epidermis generallyinclude three layers, commonly identified as the stratum granulosum, thestratum malpighii, and the stratum germinativum. Once a drug or othersubstance penetrates below the stratum corneum, there is substantiallyless resistance to permeation into the subsequent layers of the skin andeventual absorption by the body. Thus, delivery of a substance below thestratum corneum can be an effective system for administering somesubstances, and particularly some vaccines, to the body. The presentinvention is primarily directed to a device and method for delivering asubstance, and particularly a pharmaceutical agent, into or below thestratum corneum for administering the substance or pharmaceutical agentto the patient. Preferably, the device and method of the inventionpierce the stratum corneum substantially without penetrating the dermisto target the tissue layers below the stratum corneum. It is ofpotential benefit for vaccines to target presentation of antigen tovarious antigen presenting cells and other immunostimulatory sites, suchas Langerhans cells and intraepithelial cells, as well as proximaldelivery of adjuvants.

Referring to FIG. 1, the device 10 includes a body portion 12 and acover 14. The body 12 includes a bottom wall 16, side walls 18 and a topwall 20 to form a reservoir 30. The bottom wall 16 includes a pluralityof spaced apart openings 22 extending completely through the bottom wall16. The openings 22 are arranged in an array of rows and columns. Theopenings are generally uniformly spaced apart, although the spacing canbe non-uniform or it can alternate between small and large.

In the embodiment of FIGS. 1-3A, a plurality of hollow microneedles 24are provided on the bottom surface 26 of the bottom wall 16 to form anarray. Each of the microneedles 24 include a passage or opening 28passing through the length of the microneedle 24 and communicating withthe opening 22 in the bottom wall 16. The openings 22 and 28 define acontinuous channel to communicate with the reservoir 30 to access thefluid in the reservoir 30. The openings 22 and 28 have a diametersufficient to allow a fluid to pass from the reservoir to themicroneedle tips at a suitable rate to deliver the substance to theskin. The dimensions of the openings 22 and 28 will depend on thesubstance being administered and the rate of absorption for thesubstance by the tissue.

In the embodiment shown in FIGS. 3 and 3A, microneedles 24 are formedfrom a substrate such as a silicon wafer or plastic substrate. Themicroneedles are attached to the bottom wall 16 of the body 12. Infurther embodiments, the microneedles can be integrally formed with thebottom wall so that the substrate of the microneedles can form thebottom wall of the body.

As shown in FIG. 3, the side walls 18 in the embodiment illustratedextend substantially perpendicular to the bottom wall 16 and are coupledto the top wall 20 to define the reservoir 30. In the embodimentillustrated, intermediate walls 32 extend between the bottom wall 16 andthe top wall 20 to divide the reservoir 30 into three separate chambers34. Preferably, the intermediate walls 32 prevent fluid communicationbetween the adjacent chambers 34.

The top wall 20 includes several openings 36, with each opening 36defining a passageway into one of the chambers 34. A coupling member 38is attached to the top wall 20 surrounding each of the openings 36. Inthe embodiment illustrated, the coupling members 38 are externallythreaded Luer lock type fittings as known in the art. Alternatively,other coupling members can be used, such as rubber, septum or one-wayvalve.

A flexible cover sheet 40 having an adhesive layer 42 is attached to thetop wall 20 to form an adhesive patch for attaching the device to theskin of a patient. As shown in FIGS. 1 and 2, the cover sheet 40 has adimension greater than the dimension of the body portion 12 so that thecover sheet 40 has an overhanging edge portion 41 extending beyond theedges of the body 12 with an exposed area of adhesive. The cover sheet40 has a length and width greater than the body portion 12 to enable theadhesive layer 42 of the overhanging portion 41 to completely surroundthe body portion 12 and adhere to the skin of the patient and therebyattach the delivery device to the patient. The adhesive 42 is generallya pressure sensitive adhesive which will not irritate the skin and canbe easily removed from the skin without injury. A release sheet can beattached to the overhanging edge portion 41 which can be peeled away toexpose the adhesive prior to use. In further embodiments, the coversheet overhangs the body portion 12 at opposite ends.

The removable cover 14 in the embodiment of FIGS. 1 and 3 has an outerwall 44 and a side wall 46. Side wall 46 includes a detent 48 which isreceived in a recess 50 in the side wall 18 of the body portion 12. Thecover 14 snaps onto the body portion to protect the microneedles 24 andcan be removed prior to use. A resilient pad 43 is optionally providedon the inner surface of the outer wall 44 to contact the tips of themicroneedles 24 to seal the openings in the microneedles 24 withoutdamaging the microneedles.

The delivery device 10 is generally made from a plastic material that isnon-reactive with the substance being administered. Suitable plasticmaterials include, for example, polyethylene, polypropylene, polyesters,polyamides and polycarbonates as known in the art. The microneedles canbe made from various materials as known in the art. For example,microneedles can be made from silicon, stainless steel, tungsten steel,alloys of nickel, molybdenum, chromium, cobalt, and titanium, ceramics,glass polymers and other non-reactive metals, and alloys thereof.

The length and thickness of the microneedles are selected based on theparticular substance being administered and the thickness of the stratumcorneum in the location where the device is to be applied. Preferably,the microneedles penetrate the stratum corneum substantially withoutpenetrating or passing through the epidermis. The microneedles can havea length for penetrating the skin up to about 250 microns. Suitablemicroneedles have a length of about 5 to 200 microns. Typically, themicroneedles have a length of about 5 to about 100 microns, andgenerally in the range of about 50 to 100 microns. The microneedles inthe illustrated embodiment have a generally conical shape. Inalternative embodiments, the microneedles can be triangles, flat bladesor pyramids. Typically, the microneedles are perpendicular to the planeof the device. The width of the microneedles can be about 15 to 40 gaugeto obtain optimum penetration of the skin.

As shown in FIG. 2, the microneedles are typically spaced apartuniformly in rows and columns to form an array for contacting the skinand penetrating the stratum corneum. The spacing between themicroneedles can be varied depending on the substance being administeredeither on the surface of the skin or within the tissue of the skin.Typically, the microneedles are spaced a distance of about 0.05 mm toabout 5 mm.

The device 10 in the embodiment of FIGS. 1-3 includes three chambers 34for administering different substances to the skin. Each array ofmicroneedles corresponding to each of the chambers 34 are spaced apart adistance to avoid mixing and interaction between the differentsubstances being administered.

Referring to FIG. 3, the chambers 34 can be filled with a suitablesubstance from a suitable supply container through the coupling member38. A syringe 52 having a suitable outlet is attached to the couplingmember 38. The syringe 52 is a standard syringe as known in the artwhich includes a syringe barrel 56, a plunger and plunger rod assembly58 and a coupling complementing the coupling member 38, which in theillustrated embodiment is a Luer lock collar 54. The Luer lock collar 54can be integrally molded with the syringe barrel or can be a separatecollar which is snapped onto the tip 60 of the syringe barrel. Thesyringe barrel can be made of any suitable material including, forexample, glass or plastic. The Luer lock collar 54 is threaded onto thecoupling member 38 to form a fluid-tight seal. The substance in thesyringe is injected through the opening 36 into the chamber 34. Asuitable check valve 61 or other closure can be included in the couplingmember 38 to prevent the backflow of the substance from the chamber 34.

In further embodiments, the chamber 34 can include a dried orlyophilized pharmaceutical agent 62. The dried pharmaceutical agent 62can be applied as a coating on the bottom, top or side wall of thechamber or placed loosely within the chamber. A suitable solvent ordiluent such as distilled water or a saline solution is injected throughthe opening 36 into the chamber 34 shortly before or during use tosolubilize and reconstitute the pharmaceutical agent. The solvent ordiluent can be injected into the chamber 34 from a syringe or othercontainer.

Typically, the microneedles are uniformly spaced apart to form an arrayand have a substantially uniform length and width. In a furtherembodiment shown in FIG. 4, the microneedles have varying lengths topenetrate the skin at different depths. Varying the length of themicroneedles allows the pharmaceutical agent to be delivered atdifferent depths in the skin and can increase the effectiveness of theinjection. A microneedle device with microneedles of different lengthsis particularly effective in delivering a vaccine into the cells into orbelow the stratum corneum to increase the immunological efficiency ofthe vaccine by targeting an optimum absorption site. The microneedlescan have lengths ranging from about 10 microns to about 40 microns. Themicroneedles are preferably arranged in the array with alternatinglengths. Generally, the array includes microneedles having two differentlengths. In other embodiments, the array can have microneedles ofseveral lengths ranging from about 10 microns to about 40 microns. Theeffectiveness of the presentation of antigens to Langerhans cells isgenerally increased by providing the microneedles in varying lengthssince the delivery of the vaccine to the optimum site is increased.

A substance is delivered to a patient using the device of FIGS. 1-4 byplacing the microneedles against the skin and pressing or rubbing toenable the microneedles to penetrate the stratum corneum. The coversheet 40 is attached to the skin by the adhesive. A syringe 52 or otherdispensing container is coupled to the device 12 and the substance isintroduced into the chambers 34 and through the microneedles 24. Asuitable dispensing container can be, for example, a dispenser sold byBecton Dickinson and Company under the tradename Uniject. The syringe 52is able to apply sufficient force to deliver the substance directly intothe skin below the stratum corneum without the microneedles penetratingthe dermis. The force is applied to provide a rapid delivery of thesubstance into the intradermal layer below the stratum corneum so thatthe device 12 can be removed from the skin after a short period of time.It typically is unnecessary to have the device remain attached to theskin for extended periods of time as in conventional sustained releasedevices. Alternatively, the device can remain attached to sufficienttime to allow the substance to be absorbed into the skin.

In further embodiments, the syringe is used to fill the chambers with apharmaceutical agent or diluent and is then removed from the device.Then the device is pressed against the skin so that the microneedlespenetrate the stratum corneum. The pressure applied to the deviceenables the substance to be delivered below the stratum corneum. Instill further embodiments, the device is rubbed against the skin toabrade the stratum corneum to enhance the delivery of the substance.

A further embodiment of the intradermal delivery device is illustratedin FIGS. 5-7- Referring to FIGS. 5 and 6, the transdermal deliverydevice 70 includes a substantially flat base 72 having an array ofmicroneedles 74 for the delivery of the substance being administered.Unlike the embodiment of FIG. 1, the microneedles 74 are substantiallysolid with no openings or passages through the microneedles. A centralinlet port 76 is positioned in substantially the center of the base 72.A coupling member 78, such as a Luer lock collar, is attached to thebase 72 over the inlet port 76 for supplying a substance to themicroneedle 74. A suitable container having an internally threaded Luerlock collar 82 is provided for coupling with the collar 78 andintroducing a substance through the inlet port 76 to the microneedle 74.The container 80 is illustrated as a flexible plastic container whichcan be compressed to force the substance from the container through theinlet port 76. Alternatively, a syringe having a Luer lock collar can beused for introducing the substance through the inlet port 76. Anoptional closure cap 84 can be removably attached to the Luer lock 78 totemporarily close the inlet port 76. The cap 84 can be an externallythreaded cap for engaging the threads on the Luer lock 78 or can be astopper-like member for fitting into the passageway of the Luer lock 78.

A flexible sheet material 86 having an adhesive layer 88 is applied overthe upper surface of the base 72 and is attached to the base by theadhesive 88. As shown in FIGS. 5 and 6, the sheet 86 is larger than thedimension of the base 72 and overlaps on each of the sides to provide anexposed area 87 of adhesive for attaching the device to the skin of apatient. A removable cover 90 encloses the microneedles 74 to protectthe microneedles from damage prior to use. In the embodimentillustrated, the cover 90 has an outer wall 92 and side walls 94extending substantially perpendicular to the outer wall 92. The upperends of the side wall 94 attach to the adhesive layer 88 of the sheet 86to enclose the microneedles 74. The cover 90 can be separated from theadhesive 88 prior to use to expose the microneedles 74.

Referring to FIG. 7, the bottom surface 96 of the base 72 is providedwith a plurality of channels 98 formed in the bottom surface. Thechannels 98 extend between the microneedles 74 from the inlet port 76outwardly toward the edges of the base 72. In the embodimentillustrated, eight channels are illustrated extending substantiallyradially outward from the inlet port 76. In further embodiments,additional channels can be included branching outward from the channels98 to direct the substance being administered to the microneedles 74.The channels 98 are illustrated as being straight, although in furtherembodiments, the channels can be curved and branched depending on thedimension of the base 72, the distribution of the microneedles 74, andthe desired distribution of the substance being administered.

The channels 98 extend between the microneedles 74 to supply themicroneedles with the substance being administered. In use, the base 72is applied to the skin of the patient being treated so that themicroneedles 74 penetrate the stratum corneum. The base 72 can bepressed against the skin to cause the microneedles to penetrate thestratum corneum and define a delivery site into the intradermal tissue.The adhesive 88 of the sheet 86 is pressed against the skin to securethe base to the skin over the delivery site and form a seal around theperimeter of the base 72.

In further embodiments of the invention, the base may be moved or rubbedduring attachment to the skin to abrade the outermost portion of thestratum corneum of the skin and thereby enhance the penetration of themicroneedles through the stratum corneum and the delivery of thepharmaceutical agent to the epidermis. Abrading the skin to remove aportion of the stratum corneum enhances absorption of a vaccine topromote an immune response. After the base is attached to the skin, thesubstance is supplied through the port 76 from a syringe or othercontainer to feed the substance along the channels 98 and to themicroneedles 74. The force supplied by the syringe or other containerused for introducing the substance through the inlet port 76 directs thesubstance to the areas in the vicinity of the microneedles 74. Thechannels 98 direct the substance to the abraded area of the stratumcorneum to deliver the substance to the skin for absorption by the body.

Generally, the substance being administered is a solution or dispersionof a pharmaceutical agent which is injected through the inlet port 76.Alternatively, the substance can be a fluid colloid in the form of a solor a gel. Vaccines can be delivered in any liquid form as known in theart. In a further embodiment of the invention, the channels 98 arefilled with a lyophilized or dried pharmaceutical agent. A suitablesolvent or reconstituting liquid is injected through the inlet port 76and directed along the channels 98 to dissolve and reconstitute thepharmaceutical agent. The reconstituted pharmaceutical agent is thendirected to the microneedles for delivering through the stratum corneumto the epidermis.

In a further embodiment of the invention, illustrated in FIG. 8, asyringe 100 having a syringe barrel 102 is provided with a microneedletip 106. A plunger rod 104 is provided to dispense the contents of thesyringe. The tip 106 includes a plurality of microneedles 108 having alength sufficient to penetrate the stratum corneum. In the embodimentillustrated, the needles 108 have central passages extending through thelengths of the needles for communicating with the syringe barrel 102 anddirecting the substance through the stratum corneum of the patient.

Referring to FIG. 9, a further embodiment of the invention uses asyringe 110 having a tip 112 with a Luer lock collar 114, a plunger rodassembly 116 that slides within a syringe barrel 118 to dispense thecontents. A microneedle tip 118 includes a housing 120 having an inletport with a Luer lock collar 124 in a manner similar to the embodimentof FIG. 1. A plurality of microneedles 126 are attached to the bottomsurface of the housing 120. The microneedles 126 include a channelextending through the microneedles and through the bottom surface of thehousing. The microneedles 126 are substantially the same as in theembodiment of FIG. 1. The housing 120 defines a reservoir 128 fordirecting the substance through the microneedles 126. In use, thesyringe 110 is coupled to the Luer lock collar 124 and the microneedles126 are pressed against the skin of the patient to penetrate the stratumcorneum. The plunger rod assembly 116 is then depressed to express thesubstance from the syringe through the housing 120 and through themicroneedles to deliver the substance to the skin.

The delivery device of the invention is generally designed to be adisposable, single-use device. The device can be used safely andeffectively for intradermal, especially intraepidermal, delivery of apharmaceutical agent or other substance. The device is particularlysuitable for introducing a vaccine intradermally, especiallyintraepidermally, for efficiently delivering a small amount of thevaccine antigen for presentation to the Langerhans cells. The Langerhanscells are a type of intradermally located dentritic cell which take upand transport foreign material to draining lymph nodes for furtheramplification of immune response. The length, width and spacing of themicroneedles can vary depending on the pharmaceutical agent beingadministered or required to penetrate or pierce the stratum corneum tothe optimum depth for the specific pharmaceutical agent beingadministered. When delivering a vaccine, the microneedles aredimensioned to target the optimum intradermal, especiallyintraepidermal, delivery site to promote the desired immune response.

In certain embodiments illustrated, the delivery devices include inletports for injecting a pharmaceutical agent into a reservoir and throughthe microneedles. In other embodiments, the device can be prefilled witha pharmaceutical and the tips of the microneedles can be closed with asuitable closure, such as, for example, an adhesive sheet that can bepeeled from the microneedles prior to use. Alternatively, a cover havinga soft pliable member can be attached to the bottom surface of thedevice such that the pliable member contacts the microneedles to sealthe openings. The cover can then be removed from the device prior touse.

The delivery devices of the present invention are generally clean andsterile and packaged in suitable sterile pouches. In the process ofadministering a substance, the device is removed from the sterile pouch,the cover is removed from the device, and the device is placed on theskin and secured in place by the adhesive on the outer patch. The devicecan be rubbed slightly to abrade the skin's stratum corneum layer toallow the microneedles to penetrate the skin and increase the exposureof the layers of skin below the stratum corneum for more directcommunication with the underlying tissue. The device is pressed down sothat the microneedles penetrate the skin to the desired depth. A syringeis attached to feed the substance into the reservoir and into thedesired intradermal layer of the skin. When the device contains a driedpharmaceutical agent in the reservoir, a diluent is introduced to thereservoir to solubilize or reconstitute the pharmaceutical agent. Thedevice remains in contact with the skin for a sufficient period of timeto deliver an effective amount of the substance to the patient.Thereafter, the device is removed from the skin and the area of the skinis covered with a suitable protective bandage.

The intradermal delivery device of the present invention provides areliable way to deliver individual and multiple pharmaceutical agents insmall doses by an intradermal route. The microneedles of the deliverydevice limit the penetration of the needles to prevent inadvertent deeppenetration into the tissue as in conventional needles. The microneedlesare also less painful to the patient and exhibit a lower incidence ofskin necrosis common with some DNA vaccines. The multiple chambers ofthe delivery device enable the administration of multiple vaccines,adjuvants and pharmaceutical agents simultaneously without priorreformulation or combination of the pharmaceutical agents. Administeringthe pharmaceutical agents through the skin provides efficientpresentation of antigen, vaccine or adjuvant, thereby reducing the doseof the vaccine delivery. The delivery device is particularly suitablefor DNA vaccines which may be a stable dry protein product. Currently,the only delivery route is a standard needle and syringe, or specializedequipment referred to as gene guns which require formulation of theantigen so as to remain attached to gold beads. In the illustrateddevice, a small amount of a diluent supplied to the delivery devicepropels the vaccine particles through the hollow microneedles or throughchannels to solid microneedles and into intradermal tissue.

While several embodiments have been shown to illustrate the presentinvention, it will be understood by those skilled in the art thatvarious changes and modifications can be made therein without departingfrom the scope of the invention as defined in the appended claims.

1. A delivery device for introducing a substance into the skin of apatient for delivering the substance to the patient, said devicecomprising: a top wall having at least one opening; a bottom wallcoupled to said top wall and spaced from said top wall to define areservoir therebetween for containing said substance, said bottom wallhaving a plurality of openings; a coupling member attached to said topwall for supplying said substance through said openings in said top walland into said reservoir; a check valve disposed at said coupling memberto prevent flow from said reservoir through said coupling member aplurality of microneedles coupled to said outer surface of said bottomwall and being in fluid communication with said openings in said bottomwall for directing said substance from said reservoir into the skin of apatient.
 2. The device of claim 1, wherein said coupling member is aLuer lock collar.
 3. The device of claim 2, further comprising a syringeremovably coupled to said Luer lock collar for supplying a fluid to saidreservoir and expelling the fluid through said opening in said bottomwall.
 4. The device of claim 1, further comprising at least one internalwall extending between said top and bottom walls to divide saidreservoir into at least two chambers, each of said chamberscommunicating with at least one opening in said top wall and with atleast one opening in said bottom wall.
 5. The device of claim 4, whereineach of said chambers includes a dry pharmaceutical agent.
 6. The deviceof claim 5, wherein said top wall includes a coupling member attached tosaid top wall and surrounding said openings in said top wall.
 7. Thedevice of claim 1, further comprising a flexible film having a dimensiongreater than a dimension of said top wall, said film including anadhesive layer on a bottom side thereof, and being attached to said topwall by said adhesive layer and overlying said top wall and extendingbeyond said top wall a distance whereby said film is able to attach saiddevice to the skin of a patient.
 8. The device of claim 1, furthercomprising a cover removably coupled to said bottom wall and enclosingsaid microneedles.
 9. The device of claim 8, wherein said cover includesan outer wall and at least one side wall, said side wall beingfrictionally attached to said delivery device.
 10. The device of claim1, wherein said reservoir contains a substantially dry pharmaceuticalcompound, which can be reconstituted by introducing a solvent into saidreservoir.
 11. The device of claim 1, wherein said microneedles are ofdifferent lengths.
 12. The device of claim 1, wherein said microneedlesinclude a tip for penetrating the stratum corneum of the skin and afluid passage for directing a fluid from said reservoir to said tip. 13.A device for administering a substance to the skin of a patientcomprising: a substantially planar base having a top surface, a bottomsurface and an opening extending between said top and bottom surfaces; acoupling member attached to said top surface of said base for directingsaid substance through said openings in said base and for coupling to afluid source; a check valve disposed at said coupling member to preventflow from said reservoir through said coupling member a plurality ofmicroneedles attached to and extending from said bottom surface of saidbase; and a plurality of channels formed in said bottom surface of saidbase and extending outwardly from said opening and being positionedbetween said microneedles.
 14. The device of claim 13, wherein saidcoupling member is a Luer lock collar.
 15. The device of claim 14,further comprising a syringe removably coupled to said Luer lock collarfor directing said substance through said opening in said base.
 16. Thedevice of claim 13, further comprising a flexible film having adimension greater than a dimension of said top surfaces, said filmincluding an adhesive layer on a bottom side thereof, and being attachedto said base by said adhesive layer and overlying said base andextending beyond said base a distance whereby said film is able toattach said device to the skin of a patient.
 17. The device of claim 13,further comprising a cover removably coupled to said base and enclosingsaid microneedles.
 18. The device of claim 17, wherein said coverincludes an outer wall and at least one side wall, said side wall beingfrictionally attached to said base.
 19. The device of claim 13, whereinsaid channels contain a substantially dry pharmaceutical compound, whichcan be reconstituted by introducing a solvent or carrier through saidopening in said base.
 20. The device of claim 13, wherein saidmicroneedles are of different lengths.
 21. A delivery device fordelivering a substance into a patient comprising: a syringe having asyringe barrel with an outlet tip and a plunger for dispensing saidsubstance contained in said syringe; said device includes a housingdefining a reservoir; a check valve disposed at between said syringe andsaid reservoir to prevent flow from said reservoir to said syringe; anda plurality of microneedles coupled to said outlet tip and having achannel extending through the microneedles for delivering the substanceto a patient.
 22. The device of claim 21, wherein said syringe includesa Luer lock collar and said housing having a Luer lock collar forcoupling with said syringe, said microneedles being in communicationwith said reservoir for delivering said substance to said skin.
 23. Amethod of administering a substance through the skin of a patientcomprising: providing a device having a body with a top surface, abottom surface and at least one opening extending between said top andbottom surfaces, a coupling member attached to said top surface forsupplying said substance in a forward flow through said coupling memberand into said opening; a check valve disposed at said coupling member toprevent reverse flow from said opening back through said coupling membera plurality of microneedles attached to and extending from said bottomsurface of said body; contacting said device with the skin of a patientand applying sufficient pressure for said microneedles to pierce thestratum corneum of said patient; and delivering a substance to saidmicroneedles for delivery through the skin.
 24. The method of claim 23,wherein said method further comprises coupling a container containing asubstance to said coupling member for supplying said substance to saidmicroneedles.
 25. The method of claim 24, wherein said coupling memberis a Luer lock collar and said container is a syringe.
 26. The method ofclaim 23, wherein said device further includes a plurality of channelsformed in said bottom surface of said body and extending outwardly fromsaid at least one opening, and being positioned between saidmicroneedles for directing said substance from said opening to saidmicroneedles.
 27. The method of claim 23, wherein said body includes aspaced apart top wall and bottom wall to define a chamber, and aplurality of openings in said bottom wall for directing said substanceto said microneedles.
 28. The method of claim 27, wherein saidmicroneedles include passages in communication with said openings insaid bottom wall.
 29. The method of claim 26, wherein said channelsinclude a dry pharmaceutical agent contained therein and said methodcomprises directing a solvent or diluent through said at least oneopening and along said channels to dissolve or suspend saidpharmaceutical agent.
 30. The method of claim 27, wherein said chambercontains a dry pharmaceutical agent and said method comprises feeding asolvent or diluent to said chamber to dissolve or suspend saidpharmaceutical agent.